tbuckley/cabot-search huggingface dataset:
Design of stapled peptide-based PROTACs for MDM2/MDMX atypical degradation and tumor suppression
Authors: Si Chen, Xiang Li, Yinghua Li, Xing Yuan, Chenchen Geng, Songyan Gao, Jinyang Li, Bohan Ma, Zhe Wang, Wuyuan Lu, Hong-Gang Hu
Journal: Theranostics (2022)

Rationale: Although stapled peptides offer a powerful solution to overcome the susceptibility of linear peptides to proteolytic degradation and improve their ability to cross membranes, an efficient and durable disease treatment strategy has not yet been developed due to the inevitable elimination of peptide inhibitors and rapid accumulation of target proteins.Methods: Herein we developed stapled peptide-based proteolysis-targeting chimeras (SP-PROTACs), that simultaneously exhibited improved cellular uptake and proteolytic stability attributed to the stapled peptides, and efficient target protein degradation promoted by the PROTACs.Based on the PMI peptide with dual specificity for both MDM2 and MDMX, a series of SP-PROTACs were designed.Results: Among them, the optimized SPMI-HIF2-1 exhibited similar binding affinity with MDM2 and MDMX but obviously higher helical contents, improved proteolytic stability, better cellular permeability, and a better pharmacokinetic profile compared with its linear counterpart.Importantly, SPMI-HIF2-1 could effectively kill cancer cells and inhibit tumor progression in subcutaneous and orthotopic colorectal cancer xenograft models through simultaneously promoting the atypical degradation of both MDM2 and MDMX and durable p53 activation.An FP-based binding assay and structural modeling analysis of the ternary complex suggested that SPMI-HIF2-1 simultaneously bound with the target protein and E3 ligase.Conclusion: Our findings not only provide a new class of anticancer drug candidates, but also bridge the gap and reduce the physical distance between peptides and PROTACs.
Acellularized Uvea Hydrogel as Novel Injectable Platform for Cell‐Based Delivering Treatment of Retinal Degeneration and Optimizing Retinal Organoids Inducible System
Authors: Guilan Li, Sheng Liu, Wenfei Chen, Zhijian Jiang, Yuanting Luo, Dongliang Wang, Yingfeng Zheng, Yizhi Liu
Journal: Advanced Healthcare Materials (2022)

Replenishing the retina with retinal pigment epithelial (RPE) cells derived from pluripotent stem cells (PSCs) has great promise for treating retinal degenerative diseases, but it is limited by poor cell survival and integration in vivo. Herein, porcine acellular sclera and uvea extracellular matrix (ECM) and their counterpart hydrogels are developed, and their effects on the biological behavior of human induced pluripotent stem cell (hiPSC)-derived RPE cells (hiPSC-RPE) and embryoid body (hiPSC-EB) differentiation are investigated. Both acellular ECM hydrogels have excellent biocompatibility and suitable biodegradability without evoking an obvious immune response. Most importantly, the decellularized uvea hydrogel-delivered cells' injection remarkably promotes the hiPSC-RPE cells' survival and integration in the subretinal space, rescues the photoreceptor cells' death and retinal gliosis, and restores vision in rats with retinal degeneration for a long duration. In addition, medium supplementation with decellularized uvea peptides promotes hiPSC-EBs onset morphogenesis and neural/retinal differentiation, forming layered retinal organoids. This study demonstrates that ECM hydrogel-delivered hiPSC-RPE cells' injection may be a useful approach for treating retinal degeneration disease, combined with an optimized retinal seeding cells' induction program, which has potential for clinical application.
Quantitative Assessment of Bone Marrow Activity Using 18F-FLT PET in Aplastic Anemia and Myelodysplastic Syndromes
Authors: Toshiki Tasaki, Tetsuya Tsujikawa, Naoko Hosono, Tetsuya Mori, Akira Makino, Yasushi Kiyono, Hidehiko Okazawa, Takahiro Yamauchi
Journal: Clinical Nuclear Medicine (2022)

Peripheral cytopenias are typical of blood test abnormalities associated with a variety of conditions, including aplastic anemia (AA) and myelodysplastic syndromes (MDSs). We prospectively investigated the feasibility of quantitative analysis of whole-body bone marrow activity using PET with 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT) in AA and MDS.Sixty-eight patients with cytopenia underwent 18 F-FLT PET/MRI scan, with simultaneous bone marrow aspiration and biopsy for hematopoiesis evaluation. SUVs were measured in the vertebrae (Th3, 6, and 9 and L3), bilateral iliac crests, and extremities. SUV and bone marrow pathology were compared between AA and MDS and analyzed in relation to severity of AA and prognosis of MDS.Of the 68 patients with cytopenia, 12 were diagnosed with AA, 27 with MDS, 12 with bone marrow neoplasia, 2 with myelofibrosis, and 15 with other conditions. Iliac 18 F-FLT SUVs were significantly correlated with bone marrow cell numbers and cell density ( r = 0.47, P < 0.001 and ρ = 0.65, P < 0.001, respectively). There was a significant positive correlation between iliac and vertebral SUVs in AA and MDS ( r = 0.65, P < 0.05 and r = 0.70, P < 0.001, respectively), and the slope of the regression line was significantly steeper in AA than in MDS ( P < 0.05). In AA patients, vertebral 18 F-FLT SUVs significantly decreased with disease progression, and in MDS patients, higher whole-body 18 F-FLT uptake was associated with shorter overall survival (hazards ratio, 3.18; 95% confidence interval, 1.07-9.47; P = 0.037).Quantitative whole-body bone marrow imaging using 18 F-FLT PET helps distinguish AA from MDS and assess the severity of AA and prognosis of MDS.
Analysis of Patient-Focused Information About Left Atrial Appendage Occlusion on US Hospital Web Pages
Authors: Sanket S. Dhruva, Robin Z. Ji, Joseph S. Ross, Erica S. Spatz, Rita F. Redberg
Journal: JAMA Internal Medicine (2022)

This cross-sectional study examines information provided about left atrial appendage occlusion, particularly use of the Watchman device, on publicly available US hospital web pages.
A Conflicting Case of Ophthalmoparesis
Authors: Newman Cheng
Journal: JAMA Neurology (2022)

A 37-year-old man with no known medical or drug history presented with an insidious onset of left-eye ptosis. He did not complain of headaches, facial numbness, dysarthria, facial droop, dysphagia, limb weakness or numbness. What is your diagnosis?
Dual-targeted magnetic mesoporous silica nanoparticles reduce brain amyloid-β burden via depolymerization and intestinal metabolism
Authors: Ni Liu, Xiaohan Liang, Changwen Yang, Shun Hu, Qingming Luo, Haiming Luo
Journal: Theranostics (2022)

Rationale: Active removal of excess peripheral amyloid-β (Aβ) can potentially treat Alzheimer's disease (AD).However, the peripheral clearance of Aβ using an anti-Aβ monoclonal antibody (mAb) cannot remove PET-detectable Aβ within the brain.This may be due to the inability of mAb to cross the blood-brain barrier (BBB) to degrade insoluble brain Aβ plaques and block liver dysfunction.Methods: We developed a dual-targeted magnetic mesoporous silica nanoparticle (HA-MMSN-1F12) through surface-coupled Aβ42-targeting antibody 1F12 and CD44-targeting ligand hyaluronic acid (HA).Results: HA-MMSN-1F12 had a high binding affinity toward Aβ42 oligomers (Kd = 1.27 ± 0.34 nM) and revealed robust degradation of Aβ42 aggregates.After intravenous administration of HA-MMSN-1F12 into ten-month-old APP/PS1 mice for three weeks (4 mg/kg/week), HA-MMSN-1F12 could cross the BBB and depolymerize brain Aβ plaques into soluble Aβ species.In addition, it also avoided hepatic uptake and excreted captured Aβ species through intestinal metabolism, thereby reducing brain Aβ load and neuroinflammation and improving memory deficits of APP/PS1 mice.Furthermore, the biochemical analysis showed that HA-MMSN-1F12 did not detect any toxic side effects on the liver and kidney.Thus, the efficacy of HA-MMSN-1F12 is associated with the targeted degradation of insoluble brain Aβ plaques, avoidance of non-specific hepatic uptake, and excretion of peripheral Aβ through intestinal metabolism. Conclusions:The study provides a new avenue for treating brain diseases by excreting disease-causing biohazards using intestinal metabolism.
Preparedness of Pediatric Subspecialty Fellows to Address Emotional and Mental Health Needs Among Children With Chronic Medical Conditions
Authors: Cori M. Green, JoAnna K. Leyenaar, Ashley Tucker, Laurel K. Leslie
Journal: JAMA Pediatrics (2022)

This survey study investigates pediatric subspecialty fellows’ attitudes about and perceived competence in addressing emotional and mental health needs of pediatric patients with chronic medical conditions.
Peripartum Outcomes Associated With COVID-19 Vaccination During Pregnancy
Authors: Atsuyuki Watanabe, Jun Yasuhara, Masao Iwagami, Yoshihisa Miyamoto, Yuji Yamada, Yukio Suzuki, Hisato Takagi, Toshiki Kuno
Journal: JAMA Pediatrics (2022)

The risk and benefits of COVID-19 vaccination during pregnancy are under investigation. Pooled evidence regarding neonatal and maternal outcomes in association with COVID-19 vaccination during pregnancy is scarce.
Error in Byline
Journal: JAMA Network Open (2022)

Paul K. Drain, MD, MPH; Meagan Bemer, MS; Jennifer F. Morton, MPH; Ronit Dalmat, PhD; Hussein Abdille, MBChB; Katherine K. Thomas, MS; Timsy K. Uppal, PhD; Derrick Hau, PhD; Heather R. Green, PhD; Marcellene A. Gates-Hollingsworth, BA; David P. AuCoin, PhD; Subhash C. Verma, PhD
Neoadjuvant Pembrolizumab and Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Cancer: 3-Year Median Follow-Up Update of PURE-01 Trial
Authors: Giuseppe Basile, Marco Bandini, Ewan A. Gibb, Jeffrey S. Ross, Daniele Raggi, Laura Marandino, Tiago Costa de Padua, Emanuele Crupi, Renzo Colombo, Maurizio Colecchia, Roberta Lucianò, Luigi Nocera, Marco Moschini, Alberto Briganti, Francesco Montorsi, Andrea Necchi
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The PURE-01 study (NCT02736266) pioneered the neoadjuvant immune-checkpoint inhibitor (ICI) therapy before radical cystectomy (RC) in patients with muscle-invasive urothelial bladder carcinoma (MIBC). We herein present the survival outcomes after a median follow-up of three years. Patients and Methods: The intention-to-treat (ITT) population included 155 patients. Event-free survival (EFS) was defined as the time from pembrolizumab initiation until radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy, recurrence after RC, or death. Further outcomes were recurrence-free survival (RFS) post-RC and overall survival (OS). Multivariable Cox regression analyses for EFS were performed. Kaplan–Meier analyses compared EFS outcomes according with baseline programmed cell-death-ligand-1 (PD-L1) combined positive score (CPS) and according to the molecular subtypes. Results: After a median (interquartile range, IQR) follow-up of 39 (30–47) months, 36-month EFS and OS were 74.4% [95% confidence interval (CI), 67.8–81.7] and 83.8% (95% CI, 77.8–90.2) in the ITT population, respectively. Overall, 143 (92.3%) patients underwent RC. Within the cohort of patients who did not receive additional chemotherapy (N = 125), 36-month RFS was 96.3% (95% CI, 91.6–100) for patients achieving a ypT0N0, 96.1% (95% CI, 89–100) for ypT1/a/isN0, 74.9% (95% CI, 60.2–93) for ypT2–4N0, and 58.3% (95% CI, 36.2–94.1) for ypTanyN1–3 response. EFS was significantly stratified among PD-L1 tertiles (lower tertile: 59.7% vs. medium tertile: 76.7% vs. higher tertile: 89.8%, P = 0.0013). The claudin-low and basal/squamous subtypes displayed the lowest rates of events. Conclusions: At a median follow-up of three years, PURE-01 results further confirm the sustained efficacy of neoadjuvant pembrolizumab before RC. PD-L1 expression was the strongest predictor of sustained response post-RC.
Breast Cancer Statistics, 2022
Authors: Angela N. Giaquinto, Hyuna Sung, Kimberly D. Miller, Joan L. Kramer, Lisa A. Newman, Adair Minihan, Ahmedin Jemal, Rebecca L. Siegel
Journal: CA A Cancer Journal for Clinicians (2022)

Abstract This article is the American Cancer Society’s update on female breast cancer statistics in the United States, including population‐based data on incidence, mortality, survival, and mammography screening. Breast cancer incidence rates have risen in most of the past four decades; during the most recent data years (2010–2019), the rate increased by 0.5% annually, largely driven by localized‐stage and hormone receptor‐positive disease. In contrast, breast cancer mortality rates have declined steadily since their peak in 1989, albeit at a slower pace in recent years (1.3% annually from 2011 to 2020) than in the previous decade (1.9% annually from 2002 to 2011). In total, the death rate dropped by 43% during 1989–2020, translating to 460,000 fewer breast cancer deaths during that time. The death rate declined similarly for women of all racial/ethnic groups except American Indians/Alaska Natives, among whom the rates were stable. However, despite a lower incidence rate in Black versus White women (127.8 vs. 133.7 per 100,000), the racial disparity in breast cancer mortality remained unwavering, with the death rate 40% higher in Black women overall (27.6 vs. 19.7 deaths per 100,000 in 2016–2020) and two‐fold higher among adult women younger than 50 years (12.1 vs. 6.5 deaths per 100,000). Black women have the lowest 5‐year relative survival of any racial/ethnic group for every molecular subtype and stage of disease (except stage I), with the largest Black–White gaps in absolute terms for hormone receptor‐positive/human epidermal growth factor receptor 2‐negative disease (88% vs. 96%), hormone receptor‐negative/human epidermal growth factor receptor 2‐positive disease (78% vs. 86%), and stage III disease (64% vs. 77%). Progress against breast cancer mortality could be accelerated by mitigating racial disparities through increased access to high‐quality screening and treatment via nationwide Medicaid expansion and partnerships between community stakeholders, advocacy organizations, and health systems.
Inhibiting the activation of MAPK (ERK1/2) in stressed Müller cells prevents photoreceptor degeneration
Authors: Shaoxue Zeng, Ting Zhang, Yingying Chen, Joshua Chu-Tan, Kaiyu Jin, So-Ra Lee, Michelle X Yam, Michele C. Madigan, Nilisha Fernando, Adrian Cioanca, Fanfan Zhou, Meidong Zhu, Junjun Zhang, Riccardo Natoli, Xiaohui Fan, Ling Zhu, Mark C Gillies
Journal: Theranostics (2022)

Rationale: Müller cells play an essential role in maintaining the health of retinal photoreceptors.Dysfunction of stressed Müller cells often results in photoreceptor degeneration.However, how these cells communicate under stress and the signalling pathways involved remain unclear.In this study, we inhibited the MAPK (ERK1/2) signalling, mainly activated in Müller cells, evaluated the protective effects on the photoreceptors and further explored the signalling communication between stressed Müller cells and degenerating photoreceptors.Methods: We evaluated the changes of MAPK (ERK1/2) signalling and its downstream targets in human retinal explants treated with PD98059, a specific phosphorylated ERK1/2 inhibitor, by western blot and immunostaining.We further assessed photoreceptor degeneration by TUNEL staining and outer nuclear layer thickness.We also injected PD98059 into the eyes of mice exposed to photo-oxidative stress.We evaluated the protective effects on photoreceptor degeneration by optical coherence tomography (OCT) and electroretinography (ERG).The crosstalk between Müller cells and photoreceptors was further dissected based on the changes of transcription factors by RNA sequencing and protein profiles of multiple signalling pathways.Results: We found that MAPK (ERK1/2) signalling was mainly activated in Müller cells under stress, both ex vivo and in vivo.PD98059 inhibited the phosphorylation of ERK1/2, reduced expression of the gliotic marker glial fibrillary acidic protein (GFAP) in Müller cells and increased levels of the neuroprotective factor, interphotoreceptor retinoid-binding protein (IRBP) in photoreceptors.Inhibition of pERK1/2 also reduced retinal photo-oxidative damage in mice retinas assessed by OCT and ERG.We also identified that the JAK/STAT3 signalling pathway might mediate signalling transduction from Müller cells to photoreceptors.Conclusion: MAPK (ERK1/2) deactivation through chemical inhibition, mainly in stressed Müller cells, can alleviate gliosis in Müller cells and restore the expression of IRBP in photoreceptors, which appears to prevent retinal degeneration.Our findings suggested a new way to prevent photoreceptor degeneration by manipulating the stress response in Müller cells.
Myeloid-derived suppressor cells prevent disruption of the gut barrier, preserve microbiota composition, and potentiate immunoregulatory pathways in a rat model of experimental autoimmune encephalomyelitis
Authors: Dušan Radojević, Marina Bekić, Alisa Gruden-Movsesijan, Nataša Ilić, Miroslav Dinić, Aleksandar Bisenić, Nataša Golić, Dragana Vučević, Jelena Đokić, Sergej Tomić
Journal: Gut Microbes (2022)

Over-activated myeloid cells and disturbance in gut microbiota composition are critical factors contributing to the pathogenesis of Multiple Sclerosis (MS). Myeloid-derived suppressor cells (MDSCs) emerged as promising regulators of chronic inflammatory diseases, including autoimmune diseases. However, it remained unclear whether MDSCs display any therapeutic potential in MS, and how this therapy modulates gut microbiota composition. Here, we assessed the potential of in vitro generated bone marrow-derived MDSCs to ameliorate experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats and investigated how their application associates with the changes in gut microbiota composition. MDSCs differentiated with prostaglandin (PG)E2 (MDSC-PGE2) and control MDSCs (differentiated without PGE2) displayed strong immunosuppressive properties in vitro, but only MDSC-PGE2 significantly ameliorated EAE symptoms. This effect correlated with a reduced infiltration of Th17 and IFN-γ-producing NK cells, and an increased proportion of regulatory T cells in the CNS and spleen. Importantly, both MDSCs and MDSC-PGE2 prevented EAE-induced reduction of gut microbiota diversity, but only MDSC-PGE2 prevented the extensive alterations in gut microbiota composition following their early migration into Payer's patches and mesenteric lymph nodes. This phenomenon was related to the significant enrichment of gut microbial taxa with potential immunoregulatory properties, as well as higher levels of butyrate, propionate, and putrescine in feces. This study provides new insights into the host–microbiota interactions in EAE, suggesting that activated MDSCs could be potentially used as an efficient therapy for acute phases of MS. Considering a significant association between the efficacy of MDSC-PGE2 and gut microbiota composition, our findings also provide a rationale for further exploring the specific microbial metabolites in MS therapy.
Associations between Pretreatment Body Composition Features and Clinical Outcomes among Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Immune Checkpoint Blockade
Authors: Yasser Ged, Alejandro Sanchez, Sujata Patil, Andrea Knezevic, Emily Stein, Stacey Petruzella, Kate Weiss, Cihan Duzgol, Joshua Chaim, Oguz Akin, Marina Mourtzakis, Michael T. Paris, Jessica Scott, Fengshen Kuo, Ritesh Kotecha, A. Ari Hakimi, Chung-Han Lee, Robert J. Motzer, Martin H. Voss, Helena Furberg
Journal: Clinical Cancer Research (2022)

Abstract Purpose: High body mass index (BMI) may lead to improved immune-checkpoint blockade (ICB) outcomes in metastatic clear cell renal cell carcinoma (mccRCC). However, BMI is a crude body size measure. We investigated BMI and radiographically assessed body composition (BC) parameters association with mccRCC ICB outcomes. Experimental Design: Retrospective study of ICB-treated patients with mccRCC. BMI and BC variables [skeletal muscle index (SMI) and multiple adiposity indexes] were determined using pretreatment CT scans. We examined the associations between BMI and BC variables with ICB outcomes. Therapeutic responses per RECIST v1.1 were determined. We compared whole-transcriptomic patterns with BC variables in a separate cohort of 62 primary tumor samples. Results: 205 patients with mccRCC were included in the cohort (74% were male, 71% were overweight/obese, and 53% were classified as low SMI). High-BMI patients experienced longer overall survival (OS) than normal-weight patients [unadjusted HR, 0.66; 95% confidence interval (CI), 0.45–0.97; P = 0.035]. The only BC variable associated with OS was SMI [unadjusted HR comparing low vs. high SMI 1.65 (95% CI: 1.13–2.43); P = 0.009]. However, this OS association became nonsignificant after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium score and line of therapy. No OS association was seen for adiposity and no BC variable was associated with progression-free survival or radiological responses. Tumors from patients with low SMI displayed increased angiogenic, inflammatory, and myeloid signals. Conclusions: Our findings highlight the relevance of skeletal muscle in the BMI paradox. Future studies should investigate if addressing low skeletal muscle in metastatic patients treated with ICB can improve survival.
Cost-effectiveness of Aducanumab and Donanemab for Early Alzheimer Disease—Estimating the True Value
Authors: Edward R. Scheffer Cliff, Amar H. Kelkar
Journal: JAMA Neurology (2022)

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Association of Antidepressant Use During Pregnancy With Risk of Neurodevelopmental Disorders in Children
Authors: Elizabeth A. Suarez, Brian T. Bateman, Sonia Hernández-Díaz, Loreen Straub, Katherine L. Wisner, Kathryn J. Gray, Page B. Pennell, Barry Lester, Christopher J. McDougle, Yanmin Zhu, Helen Mogun, Krista F. Huybrechts
Journal: JAMA Internal Medicine (2022)

Antidepressant use during pregnancy has been associated with neurodevelopmental disorders in children in some studies. However, results may be explained by uncontrolled confounding by parental mental health status, genetics, and environmental factors.